Nanoparticle Delivery of STAT3 Alleviates Pulmonary Hypertension in a Mouse Model of Alveolar Capillary Dysplasia.
Nanoparticle Delivery of STAT3 Alleviates Pulmonary Hypertension in a Mouse Model of Alveolar Capillary Dysplasia.
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DOI：
10.1161/circulationaha.121.053980
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发表时间：
2021-08-17
期刊：
影响因子：
37.8
通讯作者：
Kalinichenko VV
中科院分区：
文献类型：
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作者：
Sun F;Wang G;Pradhan A;Xu K;Gomez-Arroyo J;Zhang Y;Kalin GT;Deng Z;Vagnozzi RJ;He H;Dunn AW;Wang Y;York AJ;Hegde RS;Woods JC;Kalin TV;Molkentin JD;Kalinichenko VV
肺动脉高压（PH）是肺泡毛细血管发育不良伴肺静脉错位（ACDMPV）患者的常见并发症，ACDMPV是一种与FOXF 1基因突变相关的严重先天性疾病。虽然肺泡微血管的丧失导致ACDMPV患者的PH，但尚不清楚增加新生儿肺血管生成是否可以预防PH和右心室（RV）肥大。我们使用超声心动图、RV导管插入术、免疫染色和生化方法来检查携带S52 F Foxf 1突变（在ACDMPV患者中鉴定）的Foxf 1 WT/S52 F小鼠的肺和心脏重塑以及RV输出量。采用囊胚互补法检测Foxf 1 WT/S52 F突变体胚胎干细胞（ESCs）在体内分化为呼吸细胞系的能力。血管内递送具有非整合Stat 3表达载体的纳米颗粒用于改善Foxf 1 WT/S52 F小鼠中的新生儿肺血管生成，并确定其对PH和RV肥大的影响。Foxf 1 WT/S52 F小鼠出生后出现PH和RV肥大。Foxf 1 WT/S52 F小鼠PH的严重程度与死亡率、低体重、肺动脉肌化和肺组织中胶原沉积增加直接相关。在人ACDMPV肺中发现了增加的纤维化重塑。携带S52 F Foxf 1突变的小鼠ESC用于通过胚泡互补产生嵌合体，并证明Foxf 1 WT/S52 F ESC具有分化为肺肌成纤维细胞的倾向。血管内递送携带Stat 3 cDNA的纳米颗粒保护Foxf 1 WT/S52 F小鼠免于RV肥大和PH，改善存活率并减少纤维化肺重塑。增加新生儿肺血管生成的纳米颗粒疗法可被认为可预防ACDMPV中的PH。
Pulmonary hypertension (PH) is a common complication in patients with Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV), a severe congenital disorder associated with mutations in the FOXF1 gene. While the loss of alveolar microvasculature causes PH in ACDMPV patients, it is unknown whether increasing neonatal lung angiogenesis could prevent PH and right ventricular (RV) hypertrophy. We used echocardiography, RV catheterization, immunostaining and biochemical methods to examine lung and heart remodeling and RV output in Foxf1WT/S52F mice carrying the S52F Foxf1 mutation (identified in ACDMPV patients). The ability of Foxf1WT/S52F mutant embryonic stem cells (ESCs) to differentiate into respiratory cell lineages in vivo was examined using blastocyst complementation. Intravascular delivery of nanoparticles with a non-integrating Stat3 expression vector was used to improve neonatal pulmonary angiogenesis in Foxf1WT/S52F mice and determine its effects on PH and RV hypertrophy. Foxf1WT/S52F mice developed PH and RV hypertrophy after birth. The severity of PH in Foxf1WT/S52F mice directly correlated with mortality, low body weight, pulmonary artery muscularization and increased collagen deposition in the lung tissue. Increased fibrotic remodeling was found in human ACDMPV lungs. Mouse ESCs carrying the S52F Foxf1 mutation were used to produce chimeras via blastocyst complementation and to demonstrate that Foxf1WT/S52F ESCs have a propensity to differentiate into pulmonary myofibroblasts. Intravascular delivery of nanoparticles carrying Stat3 cDNA protected Foxf1WT/S52F mice from RV hypertrophy and PH, improved survival and decreased fibrotic lung remodeling. Nanoparticle therapies increasing neonatal pulmonary angiogenesis may be considered to prevent PH in ACDMPV.